CN104003947A - Sulfur/nitrogen-containing azole antifungal compound as well as preparation method and application of sulfur-containing azoles antifungal compound - Google Patents
Sulfur/nitrogen-containing azole antifungal compound as well as preparation method and application of sulfur-containing azoles antifungal compound Download PDFInfo
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- C07—ORGANIC CHEMISTRY
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- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
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Abstract
The invention is a sulfur/nitrogen-containing azole antifungal compound as well as a preparation method and an application of the sulfur/nitrogen-containing azole antifungal compound, relates to the technical field of medicine. The sulfur/nitrogen-containing azole antifungal compound is a novel azole antifungal compound and has a chemical structural formula which is shown in the specification, wherein, R1 is hydrogen or a straight-chain or branched-chain saturated or unsaturated lower alkyl having 1-6 carbon atoms; R2 is selected from hydrogen, alkyl, halogen, cyano group, a nitro group, an amino and an alkoxy, can be located at the ortho, meta or para position of the benzene ring and can be monosubstituted or polysubstituted. The invention also provides a preparation method and an application of the compound. The compound disclosed by the invention has strong antifungal activity on the deep fungal, has the advantages of high efficiency, low toxicity, broad anti-fungal spectrum and the like compared with the current clinically applied antifungal drugs, and therefore, the compound can be used for the preparation of efficient antifungal agents.
Description
Technical field
The present invention relates to medical technical field, is novel azole antifungal compound-N-alkyl-N-(2-(2,4 difluorobenzene base)-2-hydroxyl-3-(1
h-1,2,4-triazol-1-yl))-propyl group-Dithiocarbamate compounds and its esters, and their preparation method and purposes.
Background technology
In recent years, widespread use along with Broad spectrum antibiotics, antitumor drug, immunosuppressor, peritoneal dialysis, organ transplantation, radiocurablely generally carry out, and the immunodeficiency diseases rapid spread of acquired immune deficiency syndrome (AIDS) especially, the sickness rate of the opportunistic deep fungal infections such as Candida albicans, cryptococcus neoformans and aspergillus fumigatus sharply rises.Deep fungal infection has risen to the third-largest communicable disease clinically, and the mankind's life and health in serious threat.The antifungal drug of at present clinical application, mostly exists that toxic side effect is large, narrow antimicrobial spectrum, easily produces the defects such as resistance, effectively antifungal drug particularly anti-deep fungal medicine extremely lack, far can not satisfy the demand.Existing antifungal drug is mainly the propylamine that acts on squalene epoxidase, acts on lanosterol 14
athe nitrogen azole of-demethylase, and act on cell walls and-1,3-
βthe lipopeptid class of glucan synthase etc.
Reported at present and clinically conventional nitrogen azole compounds have KETOKONAZOL (Ketoconazole, KCZ), fluconazole (Fluconazole, FCZ), voriconazole (Voriconazole, VCZ), itraconazole (Itraconazole, ICZ), amphotericin B (Amphotericin B, AMB) etc., but these compounds still exist, and above-mentioned toxic side effect is large, narrow antimicrobial spectrum, easily produce the defects such as resistance, for example bring into play the required dosage of drug effect larger, thereby can produce larger toxic side effect to human body.As everyone knows, the nitrogen azole compounds that structure is different has different biological activitys, so research and development are efficient, the nitrogen azole compounds of the new texture type of low toxicity and has a broad antifungal spectrum remains the study hotspot of this compounds.But so far there are no, there is nitrogen azole compounds N-alkyl-N-(2-(2,4 difluorobenzene base)-2-hydroxyl-3-(1 of anti-mycotic activity
h-1,2,4-triazol-1-yl)) report of-propyl group-Dithiocarbamate or its esters.
Summary of the invention
The object of the invention is, for deficiency of the prior art, provides a kind of azole antifungal compound and pharmacy acceptable salt thereof.
One object more of the present invention is that a kind of pharmaceutical composition is provided.
Another object of the present invention is that the preparation method of above-mentioned azole antifungal compound and pharmacy acceptable salt thereof is provided.
The 4th object of the present invention is that the purposes of above-mentioned azole antifungal compound and pharmacy acceptable salt thereof is provided.
For achieving the above object, the technical scheme that the present invention takes is:
Azole antifungal compound and a pharmacy acceptable salt thereof, described azole antifungal compound N-alkyl-N-(2-(2,4 difluorobenzene base)-2-hydroxyl-3-(1
h-1,2,4-triazol-1-yl)) chemical structure of general formula of-propyl group-Dithiocarbamate is as follows:
Wherein,
R
1for the straight or branched of hydrogen or 1-6 carbon atom is saturated or unsaturated low alkyl group;
R
2be selected from hydrogen, alkyl, halogen, cyano group, nitro, alkoxyl group, can be positioned at phenyl ring neighbour,, contraposition, can be monosubstituted or polysubstituted;
Wherein, alkyl is the alkyl of 1-4 carbon atom;
Halogen is selected from F, Cl, Br, I;
Alkoxyl group is selected from methoxyl group, oxyethyl group, tertiary butyl oxygen base.
N-alkyl-N-of the present invention (2-(2,4 difluorobenzene base)-2-hydroxyl-3-(1
h-1,2,4-triazol-1-yl))-propyl group-Dithiocarbamate compounds or its esters can be raceme, can be also
rtype or
stype isomer.
For realizing above-mentioned second object, the technical scheme that the present invention takes is:
A pharmaceutical composition, it contains as above arbitrary described azole antifungal compound and pharmacy acceptable salt thereof, and contains conventional pharmaceutical carrier.
For realizing above-mentioned the 3rd object, the technical scheme that the present invention takes is:
As above arbitrary described azole antifungal compound and the preparation method of pharmacy acceptable salt thereof, comprise the following steps:
(1) prepare intermediate 1-(1
h-1,2,4-triazol-1-yl)-2-(2,4 difluorobenzene base)-3-(
n-alkylamino)-2-alcohol (
5),
(2) intermediate and the CS that prepared by step (1)
2, triethylamine ice bath reaction in ethanol, then add various replacement bromobenzyls, under room temperature condition, reaction generates target compound.
Reaction scheme is as follows;
For realizing above-mentioned the 4th object, the technical scheme that the present invention takes is:
As above arbitrary described azole antifungal compound and pharmacy acceptable salt thereof the application in preparation treatment fungi infestation medicine.
Described fungi is Candida albicans bacterium, Candida parapsilosis bacterium, Candida glabrata, cryptococcus neoformans, Sabouraudites lanosus, trichophyton or aspergillus fumigatus.
The invention has the advantages that:
1, the compounds of this invention is strong to deep fungal anti-mycotic activity, compares with the antifungal drug of current clinical application, has the advantages such as efficient, low toxicity, anti-fungus spectra be wide, therefore can be used for preparing efficient antifungal drug;
2, the preparation method of the compounds of this invention is simple and productive rate is high, and the compound anti-mycotic efficiency preparing is good.
Embodiment
Below embodiment provided by the invention is elaborated.
the preparation of embodiment 1 the compounds of this invention
(1) 1-(1
h-1,2,4-triazol-1-yl)-2-(2,4 difluorobenzene base)-3-(
n-methylamino)-2-alcohol
1-[2-(2,4 difluorobenzene base)-2,3-epoxypropyl]-1
h-1,2,4-triazole mesylate 21g, with methylamine 10mL, triethylamine 20mL, reflux 6-8 hour in 300mL ethanol, steams and desolventizes after completion of the reaction, extracts 100mL * 2 washing by 200mL ethyl acetate, anhydrous sodium sulfate drying, filters, and steams except ethyl acetate, obtains oily 1-(1
h-1,2,4-triazol-1-yl)-2-(2,4 difluorobenzene base)-3-(
n-methylamino)-2-alcohol 11.96g, yield 68.0%.
Preparation N-methyl-N-(2-(2,4 difluorobenzene base)-2-hydroxyl-3-(1
h-1,2,4-triazol-1-yl))-propyl group-Dithiocarbamate (compound 6a in table 1):
In the mono-neck bottle of 50mL, put into magneton, add 10mL dehydrated alcohol, 0.536 g 1-(1
h-1,2,4-triazol-1-yl)-2-(2,4 difluorobenzene base)-3-(
n-methylamino)-2-alcohol (2mmol).After ice-water bath 10min, under magnetic agitation, splash into 0.12mL dithiocarbonic anhydride (2mmol) fast, maintain ice bath and stir 30min.Get bromobenzyl 170 mg(1mmol) add in bottle, splash into 0.42mL triethylamine (3mmol), remove ice bath, heating in water bath to 60 ℃, TLC detection reaction, reacts complete after about 2h.
After completion of the reaction, solvent evaporated, adds 50mL methylene dichloride and dissolves, and 10% citric acid solution, saturated sodium carbonate solution, 10% citric acid solution, each 40mL of saturated nacl aqueous solution wash successively.After anhydrous sodium sulfate drying, filter, solvent evaporated, adds 20mL ether and solidifies rear suction filtration, and 45mL ether divides washing solid 3 times, obtains end product, and drying under reduced pressure obtains 303.8 mg, yield 70.0%.
Preparation N-methyl-N-(2-(2,4 difluorobenzene base)-2-hydroxyl-3-(1
h-1,2,4-triazol-1-yl))-propyl group-aminodithioformic acid-2-fluoro-methylbenzyl ester (compound 6b in table 1):
The 2-fluorine bromobenzyl of take is raw material, and concrete preparation method is with the preparation of compound 6a, yield 65.5%.
Preparation N-methyl-N-(2-(2,4 difluorobenzene base)-2-hydroxyl-3-(1
h-1,2,4-triazol-1-yl))-propyl group-aminodithioformic acid-3-fluoro-methylbenzyl ester (compound 6c in table 1):
The 3-fluorine bromobenzyl of take is raw material, and concrete preparation method is with the preparation of compound 6a, yield 65.0%.
Preparation N-methyl-N-(2-(2,4 difluorobenzene base)-2-hydroxyl-3-(1
h-1,2,4-triazol-1-yl))-propyl group-aminodithioformic acid-4-fluoro-methylbenzyl ester (compound 6d in table 1):
The 4-fluorine bromobenzyl of take is raw material, and concrete preparation method is with the preparation of compound 6a, yield 65.2%.
Preparation N-methyl-N-(2-(2,4 difluorobenzene base)-2-hydroxyl-3-(1
h-1,2,4-triazol-1-yl))-propyl group-aminodithioformic acid-2-benzyl chloride ester (compound 6e in table 1):
The 2-chlorine bromobenzyl of take is raw material, and concrete preparation method is with the preparation of compound 6a, yield 60.5%.
Preparation N-methyl-N-(2-(2,4 difluorobenzene base)-2-hydroxyl-3-(1
h-1,2,4-triazol-1-yl))-propyl group-aminodithioformic acid-3-benzyl chloride ester (compound 6f in table 1):
The 3-chlorine bromobenzyl of take is raw material, and concrete preparation method is with the preparation of compound 6a, yield 62.3%.
Preparation N-methyl-N-(2-(2,4 difluorobenzene base)-2-hydroxyl-3-(1
h-1,2,4-triazol-1-yl))-propyl group-aminodithioformic acid-4-benzyl chloride ester (compound 6g in table 1):
The 4-chlorine bromobenzyl of take is raw material, and concrete preparation method is with the preparation of compound 6a, yield 62.5%.
Preparation N-methyl-N-(2-(2,4 difluorobenzene base)-2-hydroxyl-3-(1
h-1,2,4-triazol-1-yl))-propyl group-aminodithioformic acid-2-bromobenzyl ester (compound 6h in table 1):
The 2-bromine bromobenzyl of take is raw material, and concrete preparation method is with the preparation of compound 6a, yield 66.5%.
Preparation N-methyl-N-(2-(2,4 difluorobenzene base)-2-hydroxyl-3-(1
h-1,2,4-triazol-1-yl))-propyl group-aminodithioformic acid-3-bromobenzyl ester (compound 6i in table 1):
The 3-bromine bromobenzyl of take is raw material, and concrete preparation method is with the preparation of compound 6a, yield 64.2%.
Preparation N-methyl-N-(2-(2,4 difluorobenzene base)-2-hydroxyl-3-(1
h-1,2,4-triazol-1-yl))-propyl group-aminodithioformic acid-4-bromobenzyl ester (compound 6j in table 1):
The 4-bromine bromobenzyl of take is raw material, and concrete preparation method is with the preparation of compound 6a, yield 63.5%.
Preparation N-methyl-N-(2-(2,4 difluorobenzene base)-2-hydroxyl-3-(1
h-1,2,4-triazol-1-yl))-propyl group-aminodithioformic acid-2-methyl benzyl ester (compound 6k in table 1):
The 2-methyl bromobenzyl of take is raw material, and concrete preparation method is with the preparation of compound 6a, yield 60.5%.
Preparation N-methyl-N-(2-(2,4 difluorobenzene base)-2-hydroxyl-3-(1
h-1,2,4-triazol-1-yl))-propyl group-aminodithioformic acid-3-methyl benzyl ester (compound 6l in table 1):
The 3-methyl bromobenzyl of take is raw material, and concrete preparation method is with the preparation of compound 6a, yield 60.0%.
Preparation N-methyl-N-(2-(2,4 difluorobenzene base)-2-hydroxyl-3-(1
h-1,2,4-triazol-1-yl))-propyl group-aminodithioformic acid-4-methyl benzyl ester (compound 6m in table 1):
The 4-methyl bromobenzyl of take is raw material, and concrete preparation method is with the preparation of compound 6a, yield 61.6%.
Preparation N-methyl-N-(2-(2,4 difluorobenzene base)-2-hydroxyl-3-(1
h-1,2,4-triazol-1-yl))-propyl group-aminodithioformic acid-2-p-Nitrobenzyl (compound 6n in table 1):
The 2-nitro bromobenzyl of take is raw material, and concrete preparation method is with the preparation of compound 6a, yield 63.5%.
Preparation N-methyl-N-(2-(2,4 difluorobenzene base)-2-hydroxyl-3-(1
h-1,2,4-triazol-1-yl))-propyl group-aminodithioformic acid-3-p-Nitrobenzyl (compound 6o in table 1):
The 3-nitro bromobenzyl of take is raw material, and concrete preparation method is with the preparation of compound 6a, yield 63.0%.
Preparation N-methyl-N-(2-(2,4 difluorobenzene base)-2-hydroxyl-3-(1
h-1,2,4-triazol-1-yl))-propyl group-aminodithioformic acid-4-p-Nitrobenzyl (compound 6p in table 1):
The 4-nitro bromobenzyl of take is raw material, and concrete preparation method is with the preparation of compound 6a, yield 62.5%.
Preparation N-methyl-N-(2-(2,4 difluorobenzene base)-2-hydroxyl-3-(1
h-1,2,4-triazol-1-yl))-propyl group-aminodithioformic acid-2-cyano group benzyl ester (compound 6q in table 1):
Take 2-cyano-benzyl bromide as raw material, and concrete preparation method is with the preparation of compound 6a, yield 63.5%.
Preparation N-methyl-N-(2-(2,4 difluorobenzene base)-2-hydroxyl-3-(1
h-1,2,4-triazol-1-yl))-propyl group-aminodithioformic acid-3-cyano group benzyl ester (compound 6r in table 1):
Take 3-cyano-benzyl bromide as raw material, and concrete preparation method is with the preparation of compound 6a, yield 63.0%.
Preparation N-methyl-N-(2-(2,4 difluorobenzene base)-2-hydroxyl-3-(1
h-1,2,4-triazol-1-yl))-propyl group-aminodithioformic acid-4-cyano group benzyl ester (compound 6s in table 1):
Take 4-cyano-benzyl bromide as raw material, and concrete preparation method is with the preparation of compound 6a, yield 64.3%.
Preparation N-ethyl-N-(2-(2,4 difluorobenzene base)-2-hydroxyl-3-(1
h-1,2,4-triazol-1-yl))-propyl group-aminodithioformic acid-2-fluoro-methylbenzyl ester (compound 7a in table 1):
With 1-(1
h-1,2,4-triazol-1-yl)-2-(2,4 difluorobenzene base)-3-(
n-ethylamino)-2-alcohol and bromobenzyl are raw material, and concrete preparation method is with the preparation of compound 6a, yield 66.5%.
Preparation N-ethyl-N-(2-(2,4 difluorobenzene base)-2-hydroxyl-3-(1
h-1,2,4-triazol-1-yl))-propyl group-aminodithioformic acid-2-fluoro-methylbenzyl ester (compound 7b in table 1):
The 2-fluorine bromobenzyl of take is raw material, and concrete preparation method is with the preparation of compound 7a, yield 66.5%.
Preparation N-ethyl-N-(2-(2,4 difluorobenzene base)-2-hydroxyl-3-(1
h-1,2,4-triazol-1-yl))-propyl group-aminodithioformic acid-3-fluoro-methylbenzyl ester (compound 7c in table 1):
The 3-fluorine bromobenzyl of take is raw material, and concrete preparation method is with the preparation of compound 7a, yield 66.0%.
Preparation N-ethyl-N-(2-(2,4 difluorobenzene base)-2-hydroxyl-3-(1
h-1,2,4-triazol-1-yl))-propyl group-aminodithioformic acid-4-fluoro-methylbenzyl ester (compound 7d in table 1):
The 4-fluorine bromobenzyl of take is raw material, and concrete preparation method is with the preparation of compound 7a, yield 67.2%.
Preparation N-ethyl-N-(2-(2,4 difluorobenzene base)-2-hydroxyl-3-(1
h-1,2,4-triazol-1-yl))-propyl group-aminodithioformic acid-2-benzyl chloride ester (compound 7e in table 1):
The 2-chlorine bromobenzyl of take is raw material, and concrete preparation method is with the preparation of compound 7a, yield 62.5%.
Preparation N-ethyl-N-(2-(2,4 difluorobenzene base)-2-hydroxyl-3-(1
h-1,2,4-triazol-1-yl))-propyl group-aminodithioformic acid-3-benzyl chloride ester (compound 7f in table 1):
The 3-chlorine bromobenzyl of take is raw material, and concrete preparation method is with the preparation of compound 7a, yield 63.3%.
Preparation N-ethyl-N-(2-(2,4 difluorobenzene base)-2-hydroxyl-3-(1
h-1,2,4-triazol-1-yl))-propyl group-aminodithioformic acid-4-benzyl chloride ester (compound 7g in table 1):
The 4-chlorine bromobenzyl of take is raw material, and concrete preparation method is with the preparation of compound 7a, yield 63.5%.
Preparation N-ethyl-N-(2-(2,4 difluorobenzene base)-2-hydroxyl-3-(1
h-1,2,4-triazol-1-yl))-propyl group-aminodithioformic acid-2-bromobenzyl ester (compound 7h in table 1):
The 2-bromine bromobenzyl of take is raw material, and concrete preparation method is with the preparation of compound 7a, yield 65.5%.
Preparation N-ethyl-N-(2-(2,4 difluorobenzene base)-2-hydroxyl-3-(1
h-1,2,4-triazol-1-yl))-propyl group-aminodithioformic acid-3-bromobenzyl ester (compound 7i in table 1):
The 3-bromine bromobenzyl of take is raw material, and concrete preparation method is with the preparation of compound 7a, yield 65.2%.
Preparation N-ethyl-N-(2-(2,4 difluorobenzene base)-2-hydroxyl-3-(1
h-1,2,4-triazol-1-yl))-propyl group-aminodithioformic acid-4-bromobenzyl ester (compound 7j in table 1):
The 4-bromine bromobenzyl of take is raw material, and concrete preparation method is with the preparation of compound 7a, yield 64.5%.
Preparation N-ethyl-N-(2-(2,4 difluorobenzene base)-2-hydroxyl-3-(1
h-1,2,4-triazol-1-yl))-propyl group-aminodithioformic acid-2-methyl benzyl ester (compound 7k in table 1):
The 2-methyl bromobenzyl of take is raw material, and concrete preparation method is with the preparation of compound 7a, yield 61.5%.
Preparation N-ethyl-N-(2-(2,4 difluorobenzene base)-2-hydroxyl-3-(1
h-1,2,4-triazol-1-yl))-propyl group-aminodithioformic acid-3-methyl benzyl ester (compound 7l in table 1):
The 3-methyl bromobenzyl of take is raw material, and concrete preparation method is with the preparation of compound 7a, yield 61.0%.
Preparation N-ethyl-N-(2-(2,4 difluorobenzene base)-2-hydroxyl-3-(1
h-1,2,4-triazol-1-yl))-propyl group-aminodithioformic acid-4-methyl benzyl ester (compound 7m in table 1):
The 4-methyl bromobenzyl of take is raw material, and concrete preparation method is with the preparation of compound 7a, yield 62.6%.
Preparation N-ethyl-N-(2-(2,4 difluorobenzene base)-2-hydroxyl-3-(1
h-1,2,4-triazol-1-yl))-propyl group-aminodithioformic acid-2-p-Nitrobenzyl (compound 7n in table 1):
The 2-nitro bromobenzyl of take is raw material, and concrete preparation method is with the preparation of compound 7a, yield 64.5%.
Preparation N-ethyl-N-(2-(2,4 difluorobenzene base)-2-hydroxyl-3-(1
h-1,2,4-triazol-1-yl))-propyl group-aminodithioformic acid-3-p-Nitrobenzyl (compound 7o in table 1):
The 3-nitro bromobenzyl of take is raw material, and concrete preparation method is with the preparation of compound 7a, yield 64.0%.
Preparation N-ethyl-N-(2-(2,4 difluorobenzene base)-2-hydroxyl-3-(1
h-1,2,4-triazol-1-yl))-propyl group-aminodithioformic acid-4-p-Nitrobenzyl (compound 7p in table 1):
The 4-nitro bromobenzyl of take is raw material, and concrete preparation method is with the preparation of compound 7a, yield 65.5%.
Preparation N-ethyl-N-(2-(2,4 difluorobenzene base)-2-hydroxyl-3-(1
h-1,2,4-triazol-1-yl))-propyl group-aminodithioformic acid-2-cyano group benzyl ester (compound 7q in table 1):
Take 2-cyano-benzyl bromide as raw material, and concrete preparation method is with the preparation of compound 7a, yield 64.5%.
Preparation N-ethyl-N-(2-(2,4 difluorobenzene base)-2-hydroxyl-3-(1
h-1,2,4-triazol-1-yl))-propyl group-aminodithioformic acid-3-cyano group benzyl ester (compound 7r in table 1):
Take 3-cyano-benzyl bromide as raw material, and concrete preparation method is with the preparation of compound 7a, yield 64.0%.
Preparation N-ethyl-N-(2-(2,4 difluorobenzene base)-2-hydroxyl-3-(1
h-1,2,4-triazol-1-yl))-propyl group-aminodithioformic acid-4-cyano group benzyl ester (compound 7s in table 1):
Take 4-cyano-benzyl bromide as raw material, and concrete preparation method is with the preparation of compound 7a, yield 64.3%.
It should be noted that, while preparing all the other target compounds, adopt corresponding R
1the replacement intermediate of group
(5)and R
2the benzyl that group replaces is as raw material, and method is the same.In the embodiment of the present invention, agents useful for same is commercially available analytical pure.
The R of the compound of more than preparing
2group, productive rate and nucleus magnetic hydrogen spectrum data are in Table 1.
The R of table 1 part of compounds of the present invention
2group, productive rate and nucleus magnetic hydrogen spectrum data sheet
the pharmacological evaluation of embodiment 2 the compounds of this invention
(1) experimental technique
Adopt conventional In Vitro Bacteriostasis experimental technique, refer to: Antimicrob Agents Chemother 1995,39 (5): 1169.
(1) experimental strain
This experiment has selected following 8 kinds of common human body cause illness's standard fungal bacterial strains as screening object:
Deep fungal: Candida albicans, cryptococcus neoformans, Candida glabrata, Candida parapsilosis bacterium;
Superficial mycosis: trichophyton;
Subcutaneous fungi: gypsum shape sporidiole bacteria, fumigation aspergillus tubigensis.
(2) test method
Bacterium solution preparation:
Before experiment, a small amount of with the inoculation circle spherical bacterium such as picking cryptococcus neoformans, Candida albicans and Candida parapsilosis from the SDA substratum of 4 ℃ of preservations, be seeded on YPD substratum, in 30 ℃, grow one day, make fungi in later stage exponential phase of growth.Get in this bacterium pearl to 1 mlYEPD nutrient solution, with aforesaid method, again activate, after 16 h, with blood cell counting plate counting, with RPMI RPMI-1640, adjust bacterial concentration to 1 * 10
3～5 * 10
3individual/ml.
Thread fungus is seeded to SDA inclined-plane, and wherein, 35 ℃ of subcutis fungi and systemic fungies (fonsecaea pedrosoi, sporotrichum schenckii, aspergillus fumigatus), cultivate one week; 30 ℃ of superficial fungis (trichophyton, gypsum shape sporidiole bacteria, microsporum lanosum), cultivate two weeks.Each bacterium activates after twice by present method, add appropriate RPMI1640 nutrient solution in SDA inclined-plane, with suction pipe, blow and beat bacterium colony, fungal spore is free in RPMI1640 nutrient solution, nutrient solution, after blood cell counting plate counting, adds RPMI1640 nutrient solution and adjusts spore concentration to 1 * 10
3～5 * 10
3individual/ml.
Liquid preparation:
Tested medicine is made into 6.4 gL with DMSO respectively
-1solution ,-20 ℃ of preservations, before experiment, put 35 ℃ of incubators by liquid taking-up and melt standby.
Drug sensitive plate preparation:
Get aseptic 96 orifice plates, in No. 1 hole of every row, add RPMI 1,640 200 μ l and make blank; 3～No. 12 hole respectively adds freshly prepared bacterium liquid 100 μ l; No. 2 hole test-compound solution 200 μ l.2～No. 11 2 times of dilutions in 10 grades, hole, make medicine final concentration in each hole be respectively 64,32,16,8,4,2,1,0.5,0.25 and 0.125mgL
-1, 2～No. 12 hole respectively adds 100 μ l bacterium liquid, and in each hole, DMSO content is all lower than 1%; Positive control, not containing medicine, is made in No. 12 holes.Each drug sensitive plate is in 35 ℃ of cultivations.
MIC value is judged:
Candidiasis, cryptococcus neoformans and thread fungus cultivate 24 h, 72 h respectively at 30 ℃ and after one week, by observing, with positive control boring ratio, the drug level in the minimum concentration hole that the OD value of take declines more than 80% is MIC
80(drug level when fungal growth 80% is suppressed).
MIC when medicine
80value surpasses while measuring concentration range, adds up by the following method: MIC
80value is higher than maximum concentration 64 mgL
-1time, count " >64 mgL
-1"; MIC
50value, for minimum concentration or when minimum concentration is following, is not distinguished, and all counts "≤0.125 mgL
-1".
The equal parallel running of above-mentioned experiment 2 to 3 times, works as MIC
80value is just accepted when can accurately repeat or only differ from a concentration, and usings higher concentration as MIC
80value
[; Work as MIC
80value differs two concentration when above, needs again to test, until meet the requirements.
(2) experimental result
In Vitro Bacteriostasis experimental result is in Table 2.From table 2, the compounds of this invention has good anti-mycotic activity, and wherein a plurality of compounds are better than Terbinafine as 6a-s, 7a-d, 8c-k, 8n, its treatment deep fungal infection effect of 8o, 8q-s, and restraining effect is very remarkable; Most compounds is far better than fluconazole and amphotericin B to the vitro inhibition activity of selected fungi, so the compounds of this invention and its esters can be used for preparing antifungal drug.
Table 2 part of compounds In Vitro Anti of the present invention fungi minimal inhibitory concentration value (MIC
80, μ g/mL)
Note: C.alb. Candida albicans bacterium, C.par. Candida parapsilosis, C.neo. cryptococcus neoformans, C.gla. Candida glabrata, A.fum. smoke aspergillus fumigatus, T.rub. trichophyton, M.gyp. gypsum shape sporidiole bacteria, FCZ. fluconazole, ICZ. itraconazole, VCZ. Wo Likang azoles, TRB. terbinafine, AB. amphotericin B.
The above is only the preferred embodiment of the present invention; it should be pointed out that for those skilled in the art, do not departing under the prerequisite of the inventive method; can also make some improvement and supplement, these improvement and supplement and also should be considered as protection scope of the present invention.
Claims (7)
1. azole compounds and salt thereof, chemical structure of general formula is as follows:
Wherein,
R
1for the straight or branched of hydrogen or 1-6 carbon atom is saturated or unsaturated low alkyl group;
R
2be selected from hydrogen, alkyl, halogen, cyano group, nitro, amino, alkoxyl group, can be positioned at phenyl ring neighbour,, contraposition, can be monosubstituted or polysubstituted;
Alkyl is the alkyl of 1-4 carbon atom;
Halogen is selected from F, Cl, Br, I;
Alkoxyl group is selected from methoxyl group, oxyethyl group, tertiary butyl oxygen base.
2. azole antifungal compound according to claim 1 and pharmacy acceptable salt thereof, is characterized in that, described compound is raceme, R type isomer or S type isomer.
3. nitrogen azole compounds according to claim 1 and salt thereof, is characterized in that the R of described compound
1and R
2group collocation is as follows respectively:
。
4. nitrogen azole compounds according to claim 1 and 2 and salt thereof, is characterized in that described salt is hydrochloride, nitrate, hydrobromate or methane sulfonates.
5. according to the arbitrary described azole antifungal compound of claim 1-4 and the preparation method of pharmacy acceptable salt thereof, it is characterized in that, comprise the following steps:
(1) prepare intermediate 1-(1
h-1,2,4-triazol-1-yl)-2-(2,4 difluorobenzene base)-3-(
n-alkylamino)-2-alcohol;
(2) intermediate and the CS that prepared by step (1)
2, triethylamine ice bath reaction in ethanol, then add various replacement bromobenzyls, under room temperature condition, reaction generates target compound.
6. according to claim 1-4 arbitrary described azole antifungal compound and the application of pharmacy acceptable salt in preparing anti-fungal infection disease medicament thereof.
7. application according to claim 6, described fungi is Candida albicans bacterium, Candida parapsilosis bacterium, Candida glabrata, cryptococcus neoformans, gypsum shape sporidiole bacteria, trichophyton or aspergillus fumigatus.
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Cited By (5)
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| CN105503753A (en) * | 2016-01-05 | 2016-04-20 | 中国人民解放军第二军医大学 | Allylamine substituted azole antifungal compound and preparation method and application thereof |
| CN105524004A (en) * | 2016-01-05 | 2016-04-27 | 中国人民解放军南京军区南京总医院 | Propylaminoazole antifungal compounds, and preparation method and application thereof |
| CN105669572A (en) * | 2016-01-05 | 2016-06-15 | 中国人民解放军第二军医大学 | Piperazinyl amine azole antifungal compound, and preparation method and application thereof |
| CN105669573A (en) * | 2016-01-05 | 2016-06-15 | 中国人民解放军第二军医大学 | Isopropyl amino azole antifungal compound, and preparation method and application thereof |
| CN107602666A (en) * | 2017-09-30 | 2018-01-19 | 中国人民解放军第二军医大学 | A kind of thioesters stapler peptide and preparation method and application |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN105503753A (en) * | 2016-01-05 | 2016-04-20 | 中国人民解放军第二军医大学 | Allylamine substituted azole antifungal compound and preparation method and application thereof |
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| CN105669573A (en) * | 2016-01-05 | 2016-06-15 | 中国人民解放军第二军医大学 | Isopropyl amino azole antifungal compound, and preparation method and application thereof |
| CN105669573B (en) * | 2016-01-05 | 2018-02-23 | 中国人民解放军第二军医大学 | A kind of isopropylamine is for azole antifungal compound and its preparation method and application |
| CN105503753B (en) * | 2016-01-05 | 2018-02-27 | 中国人民解放军第二军医大学 | A kind of allyl amine is for azole antifungal compound and its preparation method and application |
| CN107602666A (en) * | 2017-09-30 | 2018-01-19 | 中国人民解放军第二军医大学 | A kind of thioesters stapler peptide and preparation method and application |
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